ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.353+4A>G (rs760538709)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000219638 SCV000273671 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-04 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000214822 SCV000279225 uncertain significance not provided 2018-10-25 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.353+4A>G or IVS4+4A>G and consists of an A>G nucleotide substitution at the +4 position of intron 4 of the PMS2 gene. In silico analyses, which include splice predictors and evolutionary conservation, are uninformative in their assessment as to whether or not the variant is damaging.? This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 c.353+4A>G was not observed at a significant allele frequency in large population cohorts (Lek 2016). Based on currently available information, it is unclear whether PMS2 c.353+4A>G is pathogenic or benign. We consider it to be a variant of uncertain significance.
Illumina Clinical Services Laboratory,Illumina RCV000319097 SCV000469742 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae RCV000524470 SCV000552049 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-01-07 criteria provided, single submitter clinical testing This sequence change falls in intron 4 of the PMS2 mRNA. It does not directly change the encoded amino acid sequence of the PMS2 protein, but affects a highly conserved nucleotide within the consensus splice site of intron 8 (PMID: 9536098). This variant is present in population databases (rs760538709, ExAC 0.002%) but has not been reported in the literature in individuals with a PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 230211). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this is a rare intronic change with uncertain impact on splicing. It has been classified as a Variant of Uncertain Significance.
Color RCV000219638 SCV001343077 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-14 criteria provided, single submitter clinical testing

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